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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(8): 744-749, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31638572

RESUMO

Objective To demonstrate HpaA can intensify the inflammatory response and gastric mucosa injury by IL-21 from induced T cell. Methods Biopsy specimens were taken from gastric mucosa of 56 patients with H.pylori infection before and after H.pylori radical elimination by endoscope. The levels of IL-21, matrix metalloproteinase-2 (MMP2) and MMP9 from the biopsy were detected by reverse transcription PCR and Western blot analysis. Meanwhile, the recombinant HpaA was cloned, expressed and purified to stimulate the magnetic cell sorting CD3+ T cells from healthy donors' peripheral blood mononuclear cells (PBMCs), and the level of IL-21 in the supernatant fluid was detected by ELISA. Thereafter, AGS cells were cultured and Western blot analysis was performed to detect the levels of MMP2 and MMP9 in the AGS cells with human IL-21 and anti-IL-21 antibody treatment for 24 hours. Results The protein levels of IL-21 and MMP2 and MMP9 in gastric mucosa infected with H. pylori was significantly higher than that in gastric mucosa after radical treatment of H. pylori. Meanwhile, the recombinant HpaA promoted IL-21 secretion by induced CD3+T cells in vitro. IL-21 stimulated the expression of MMP2 and MMP9 in AGS cells. When IL-21 was blocked by the antibody, the levels of MMP2 and MMP9 in AGS cells decreased significantly. Conclusion HpaA plays a significant role in the gastric mucosa injury caused by H.pylori infection through IL-21 from induced T cells.


Assuntos
Adesinas Bacterianas , Mucosa Gástrica , Interleucinas , Linfócitos T , Adesinas Bacterianas/metabolismo , Mucosa Gástrica/lesões , Mucosa Gástrica/fisiopatologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Humanos , Interleucinas/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Linfócitos T/metabolismo
2.
BMC Bioinformatics ; 20(1): 448, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477013

RESUMO

BACKGROUND: Multiplexed in-situ fluorescent imaging offers several advantages over single-cell assays that do not preserve the spatial characteristics of biological samples. This spatial information, in addition to morphological properties and extensive intracellular or surface marker profiling, comprise promising avenues for rapid advancements in the understanding of disease progression and diagnosis. As protocols for conducting such imaging experiments continue to improve, it is the intent of this study to provide and validate software for processing the large quantity of associated data in kind. RESULTS: Cytokit offers (i) an end-to-end, GPU-accelerated image processing pipeline; (ii) efficient input/output (I/O) strategies for operations specific to high dimensional microscopy; and (iii) an interactive user interface for cross filtering of spatial, graphical, expression, and morphological cell properties within the 100+ GB image datasets common to multiplexed immunofluorescence. Image processing operations supported in Cytokit are generally sourced from existing deep learning models or are at least in part adapted from open source packages to run in a single or multi-GPU environment. The efficacy of these operations is demonstrated through several imaging experiments that pair Cytokit results with those from an independent but comparable assay. A further validation also demonstrates that previously published results can be reproduced from a publicly available multiplexed image dataset. CONCLUSION: Cytokit is a collection of open source tools for quantifying and analyzing properties of individual cells in large fluorescent microscopy datasets that are often, but not necessarily, generated from multiplexed antibody labeling protocols over many fields of view or time periods. This project is best suited to bioinformaticians or other technical users that wish to analyze such data in a batch-oriented, high-throughput setting. All source code, documentation, and data generated for this article are available under the Apache License 2.0 at https://github.com/hammerlab/cytokit .


Assuntos
Biomarcadores/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Microscopia de Fluorescência/métodos , Análise de Célula Única/métodos , Software , Linfócitos T/metabolismo , Tamanho Celular , Células Cultivadas , Humanos , Linfócitos T/citologia
3.
Nat Methods ; 16(9): 875-878, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31471617

RESUMO

Single-cell RNA sequencing (scRNA-seq) data are noisy and sparse. Here, we show that transfer learning across datasets remarkably improves data quality. By coupling a deep autoencoder with a Bayesian model, SAVER-X extracts transferable gene-gene relationships across data from different labs, varying conditions and divergent species, to denoise new target datasets.


Assuntos
Neoplasias da Mama/metabolismo , Biologia Computacional/métodos , Leucócitos Mononucleares/metabolismo , Análise de Sequência de RNA/normas , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Transcriptoma , Animais , Teorema de Bayes , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência de RNA/métodos
4.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Anticancer Res ; 39(9): 4957-4963, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519601

RESUMO

BACKGROUND/AIM: Adjuvant radiotherapy (RT) damages multiple layers of skin, muscle, blood vessels and blood cells that are included within the RT area. Indirect, bystander systemic effects could also develop in cells not directly hit by radiation. MATERIALS AND METHODS: Ninety-three female patients recovering from breast cancer surgery and 82 female healthy blood donors were analyzed. For identification of systemic adaptive and innate immune response, rapid and low-cost blood-based biomarkers were assayed. RESULTS: Post-operated breast cancer patients had a decreased number of circulating adaptive immune response cells but increased number of circulating immunosuppressive myeloid subpopulations. RT decreased the number of T-cells and platelets without influencing the number of immunosuppressive myeloid subpopulations. Alterations in the number and phenotypes of T-cell subpopulations were associated with SNPs. CONCLUSION: The combination of RT and immunotherapy might provide optimal treatment for cancer patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Imunidade Celular/genética , Imunidade Celular/efeitos da radiação , Contagem de Leucócitos , Fenótipo , Polimorfismo de Nucleotídeo Único , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Inata , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Radioterapia Adjuvante , Linfócitos T/imunologia , Linfócitos T/metabolismo
6.
Anticancer Res ; 39(8): 4495-4502, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366551

RESUMO

BACKGROUND/AIM: In mice, fetal liver is the first tissue of definitive erythropoiesis for definitive erythroid expansion and maturation. ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in primitive hematopoiesis and T cell development. The aim of this study was to examine whether or not Zfat is involved in definitive erythropoiesis in the fetal liver during mammalian development. MATERIALS AND METHODS: The role of Zfat during mouse fetal erythropoiesis in the fetal liver was examined using tamoxifen-inducible CreERT2 Zfat-deficient mice. RESULTS: Zfat-deficient mice exhibit moderate anemia with small and pale fetal liver through a decreased number of erythroblasts by E12.5. Apoptosis sensitivity in fetal liver erythroid progenitors was enhanced by Zfat-deficiency ex vivo. Moreover, Zfat knockdown partially inhibited CD71-/lowTer119- to CD71highTer119- transition of fetal liver erythroid progenitors with impairment in the elevation of CD71 expression. CONCLUSION: Zfat plays a critical role for erythropoiesis in the fetal liver.


Assuntos
Antígenos CD/genética , Eritropoese/genética , Fígado/crescimento & desenvolvimento , Receptores da Transferrina/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Células Eritroides/metabolismo , Células Eritroides/patologia , Desenvolvimento Fetal/genética , Feto , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Humanos , Fígado/metabolismo , Camundongos , Linfócitos T/citologia , Linfócitos T/metabolismo , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia
7.
Immunogenetics ; 71(8-9): 545-559, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31384962

RESUMO

Butyrophilins (BTN), specifically BTN3A, play a central role in the modulation of γδ T cells, which are mainly present in gut and mucosal tissues. BTN3A1 is known, for example, to activate Vγ9Vδ2 T cells by means of a phosphoantigen interaction. In the extended HLA region, three genes are located, designated BTN3A1, BTN3A2 and BTN3A3, which were also defined in rhesus macaques. In contrast to humans, rhesus monkeys have an additional gene, BTN3A3Like, which has the features of a pseudogene. cDNA analysis of 32 Indian rhesus and 16 cynomolgus macaques originating from multiple-generation families revealed that all three genes are oligomorphic, and the deduced amino acids display limited variation. The macaque BTN3A alleles segregated together with MHC alleles, proving their location in the extended (Major Histocompatibility Complex) MHC. BTN3A nearly full-length transcripts of macaques and humans cluster tightly together in the phylogenetic tree, suggesting that the genes represent true orthologs of each other. Despite the limited level of polymorphism, 15 Mamu- and 14 Mafa-BTN3A haplotypes were defined, and, as in humans, all three BTN3A genes are transcribed in PBMCs and colon tissues. In addition to regular full-length transcripts, a high number of various alternative splicing (AS) products were observed for all BTN3A alleles, which may result in different isoforms. The comparable function of certain subsets of γδ T cells in human and non-human primates in concert with high levels of sequence conservation observed for the BTN3A transcripts presents the opportunity to study these not yet well understood molecules in macaques as a model species.


Assuntos
Antígenos CD/genética , Butirofilinas/genética , Antígenos de Histocompatibilidade/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Sequência de Aminoácidos , Animais , Butirofilinas/metabolismo , Sequência Conservada , Feminino , Haplótipos , Humanos , Macaca mulatta , Masculino , Filogenia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Homologia de Sequência , Linfócitos T/metabolismo
8.
Nat Biotechnol ; 37(8): 925-936, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31375813

RESUMO

Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here, we assess the performance of a massively parallel droplet-based method for mapping transposase-accessible chromatin in single cells using sequencing (scATAC-seq). We apply scATAC-seq to obtain chromatin profiles of more than 200,000 single cells in human blood and basal cell carcinoma. In blood, application of scATAC-seq enables marker-free identification of cell type-specific cis- and trans-regulatory elements, mapping of disease-associated enhancer activity and reconstruction of trajectories of cellular differentiation. In basal cell carcinoma, application of scATAC-seq reveals regulatory networks in malignant, stromal and immune cells in the tumor microenvironment. Analysis of scATAC-seq profiles from serial tumor biopsies before and after programmed cell death protein 1 blockade identifies chromatin regulators of therapy-responsive T cell subsets and reveals a shared regulatory program that governs intratumoral CD8+ T cell exhaustion and CD4+ T follicular helper cell development. We anticipate that scATAC-seq will enable the unbiased discovery of gene regulatory factors across diverse biological systems.


Assuntos
Células da Medula Óssea/metabolismo , Cromatina/química , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Linhagem Celular , Simulação por Computador , Regulação da Expressão Gênica , Hematopoese , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos Mononucleares , Fatores de Transcrição/metabolismo
9.
Genome Biol ; 20(1): 165, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405383

RESUMO

To fully utilize the power of single-cell RNA sequencing (scRNA-seq) technologies for identifying cell lineages and bona fide transcriptional signals, it is necessary to combine data from multiple experiments. We present BERMUDA (Batch Effect ReMoval Using Deep Autoencoders), a novel transfer-learning-based method for batch effect correction in scRNA-seq data. BERMUDA effectively combines different batches of scRNA-seq data with vastly different cell population compositions and amplifies biological signals by transferring information among batches. We demonstrate that BERMUDA outperforms existing methods for removing batch effects and distinguishing cell types in multiple simulated and real scRNA-seq datasets.


Assuntos
Aprendizado Profundo , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Algoritmos , Humanos , Leucócitos Mononucleares/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Análise de Célula Única/métodos , Linfócitos T/metabolismo
10.
Life Sci ; 232: 116628, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278946

RESUMO

AIMS: Adult T-cell leukemia (ATL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus (HTLV-1) infection. Major limitations in Doxorubicin (Dox) chemotherapy are tumor resistance and severe drug complications. Here, we combined Thymoquinone (TQ) with low concentrations of Dox and determined anticancer effects against ATL in cell culture and animal model. MAIN METHODS: HTLV-1 positive (HuT-102) and HTLV-1 negative (Jurkat) CD4+ malignant T-cell lines were treated with TQ, Dox and combinations. Viability and cell cycle effects were determined by MTT assay and flow cytometry analysis, respectively. Combination effects on mitochondrial membrane potential and generation of reactive oxygen species (ROS) were assessed. Expression levels of key cell death proteins were investigated by western blotting. A mouse xenograft model of ATL in NOD/SCID was used for testing drug effects and tumor tissues were stained for Ki67 and TUNEL. KEY FINDINGS: TQ and Dox caused greater inhibition of cell viability and increased sub-G1 cells in both cell lines compared to Dox or TQ alone. The combination induced apoptosis by increasing ROS and causing disruption of mitochondrial membrane potential. Pretreatment with N-acetyl cysteine (NAC) or pan caspase inhibitor significantly inhibited the apoptotic response suggesting that cell death is ROS- and caspase-dependent. TQ and Dox combination reduced tumor volume in NOD/SCID mice more significantly than single treatments through enhanced apoptosis without affecting the survival of mice. SIGNIFICANCE: Our combination model offers the possibility to use up to twofold lower doses of Dox against ATL while exhibiting the same cancer inhibitory effects.


Assuntos
Benzoquinonas/farmacologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T do Adulto/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Scand J Immunol ; 90(3): e12802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31269269

RESUMO

Glucose and nutrient uptake is essential in supporting T cell activation and is increased upon CD3/CD28 stimulation. As T cells from pleural effusions secondary to lung cancer show impaired function, we hypothesized that these cells might have altered expression of nutrient transporters. Here, we analysed by flow cytometry the expression of the transferrin receptor CD71, amino acid transporter CD98 and glucose transporter Glut1 and glucose uptake in pleural effusion-derived T cells from lung cancer patients, after stimulation via CD3/CD28 under normoxia or hypoxia (2% O2 ). We compared the response of T cells from pleural effusions secondary to lung cancer with that of T cells from nonmalignant effusions. In memory T cells from both groups, anti-CD3/CD28-stimulation under normoxia upregulated CD98 and CD71 expression (measured as median fluorescence intensity, MFI) in comparison with anti-CD3-stimulation. Costimulation under hypoxia tended to increase CD98 expression compared to CD3-stimulation in memory T cells from both groups. Remarkably, in the cancer group, memory T cells stimulated via CD3/CD28 under hypoxia failed to increase CD71 and Glut1 expression levels compared to the cells receiving anti-CD3 stimulation, a phenomenon that contrasted with the behaviour of memory T cells from nonmalignant effusions. Consequently, glucose uptake by memory T cells from the cancer group was not increased after CD3/CD28 stimulation under hypoxia, implying that their glycolytic metabolism is defective. As this process is required for inducing an antitumoural response, our study suggests that memory T cells are rendered dysfunctional and are unable to eliminate lung tumour cells.


Assuntos
Antígenos CD28/metabolismo , Complexo CD3/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Memória Imunológica/imunologia , Neoplasias Pulmonares/metabolismo , Derrame Pleural/metabolismo , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Linfócitos T/metabolismo
12.
Life Sci ; 231: 116688, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348950

RESUMO

The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Infecções por Helicobacter/terapia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocinas CXC/imunologia , Quimiocinas CXC/metabolismo , Mucosa Gástrica/metabolismo , Gastrite , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Receptores CXCR/imunologia , Receptores CXCR/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Estômago/patologia , Neoplasias Gástricas/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
13.
Medicine (Baltimore) ; 98(30): e16345, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348233

RESUMO

To evaluate the potential role of Pten and CD4FOXP3 T cells in prognosis from endometrial cancer.Tissue samples and clinical data were collected from 200 patients with endometrial cancer and 100 control patients with benign uterine diseases. The expressions of Pten and CD4FOXP3 T cells were quantified by immunohistochemistry and immunofluorescence. After surgery, all patients were followed up for an average of 56.3 months. Surgical effects were evaluated based on the patients' symptoms and signs. A two-sided P value < .05 was considered significant.Pten diminished and CD4FOXP3 T cells significantly accumulated with the progression of endometial cancer, in comparison to the controls. Moreover, Pten expression was negatively correlated with the count of CD4FOXP3 T cells. Pten and CD4FOXP3 T cells were correlated with clinical characteristics, including tumor stage, differentiation and associated with patients' disease-free survival.Limited data were available between the expressions of Pten and CD4FOXP3 T cells in patients with endometrial cancer. Our study findings suggested that the expressions of Pten and CD4FOXP3 T cells might become possible biomarkers for the diagnosis and prediction in endometrial cancer.


Assuntos
Neoplasias do Endométrio/patologia , Fatores de Transcrição Forkhead/imunologia , PTEN Fosfo-Hidrolase/biossíntese , Linfócitos T/imunologia , Adulto , Idoso , Biomarcadores Tumorais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Neoplasias do Endométrio/genética , Feminino , Fatores de Transcrição Forkhead/biossíntese , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , Prognóstico , Linfócitos T/metabolismo
14.
Nature ; 571(7764): 205-210, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270459

RESUMO

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.


Assuntos
Envelhecimento/fisiologia , Encéfalo/citologia , Movimento Celular , Células-Tronco Neurais/citologia , Neurogênese , Análise de Célula Única , Nicho de Células-Tronco/fisiologia , Linfócitos T/citologia , Animais , Sangue , Proliferação de Células , Células Clonais/citologia , Técnicas de Cocultura , Células Endoteliais/citologia , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Análise de Sequência de RNA , Transdução de Sinais , Linfócitos T/metabolismo , Transcriptoma/genética
15.
BMC Complement Altern Med ; 19(1): 163, 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31277636

RESUMO

BACKGROUND: Therapeutic vaccines against cervical cancer remain ineffective. Previously, we demonstrated that blocking the signalling of a cytokine, interleukin 10, at the time of immunisation elicited significantly higher numbers of antigen specific T cells and inhibited tumour growth in mice. RESULTS: In the current paper, we demonstrate, in a HPV16 E6/E7 transformed TC-1 tumour mouse model, that despite increased antigen specific T cell numbers, blocking IL-10 signalling at the time of immunisation does not increase the survival time of the TC-1 tumour bearing mice compared to mice receiving the same immunisation with no IL-10 signalling blockade. Moreover, the function of tumour infiltrating T cells isolated 3 weeks post TC-1 transplantation is more suppressed than those isolated 2 weeks after tumour inoculation. We demonstrate that synthesized caerin peptides, derived from amphibian skin secretions, 1) were able to inhibit TC-1 tumour growth both in vitro and in vivo; 2) are environmentally stable; and 3) promote the secretion of pro-inflammatory interlukine-6 by TC-1 cells. Notably caerin peptides were able to increase the survival time of TC-1 tumour bearing mice after therapeutic vaccination with a HPV16E7 peptide-based vaccine containing IL-10 inhibitor, via recruiting increased levels of T cells to the tumour site. CONCLUSION: Caerin peptides increase the efficacy of a therapeutic vaccine by recruiting more T cells to the tumour site.


Assuntos
Proteínas de Anfíbios/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Vacinas Anticâncer/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Proteínas de Anfíbios/uso terapêutico , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Vacinas Anticâncer/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Interleucina-10/antagonistas & inibidores , Interleucina-6/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Linfócitos T/metabolismo
16.
Nat Commun ; 10(1): 3081, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300673

RESUMO

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.


Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Monócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , NADPH Oxidases/genética , Adulto , Metilação de DNA/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Contagem de Leucócitos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
17.
APMIS ; 127(12): 737-745, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31273832

RESUMO

Currently, adoptive immunotherapy is considered as one of the leading treatments in cancer. Successful adoptive immunotherapy depends on producing large numbers of desired T cells ex vivo for infusion. This requires an effective protocol for maximum functional T-cell expansion while keeping the time and costs to a minimum. Current T-cell expansion protocols are diverse in their methodology, and a universal protocol of expansion is wanting. Also, new findings regarding T-cell biology, signaling, and activation have reshaped the strategies of T-cell propagation over the years, introducing new ways to expand T cells. Here, we reviewed different conditions for blood-derived polyclonal T-cell expansion so as to elucidate the influential factors of T-cell expansion and their efficacy.


Assuntos
Imunoterapia Adotiva , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Meios de Cultura , Humanos , Interleucinas/farmacologia , Neoplasias/terapia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
18.
Carbohydr Polym ; 219: 121-129, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151509

RESUMO

Galectin-3 (Gal-3) can induce T-cell activation and apoptosis and plays a role in tumor immune tolerance. Here, we demonstrate that ginseng pectins selectively inhibit Gal-3-induced T-cell apoptosis, while not affecting T-cell activation. This finding stands in contrast to that from the use of modified citrus pectin (MCP) and potato galactan (P-galactan) that inhibit both. Whereas PKC/ERK and ROS/ERK pathways are involved in both T-cell activation and apoptosis, the Ras/PI3K/Akt pathway is unique to T-cell activation. Ginseng pectins selectively inhibit the ROS/ERK pathway. Using the Sarcomar-180 mouse model in which Gal-3 expression is increased, we found that ginseng pectins (but not MCP or P-galactan) significantly promote T-cell proliferation and IL-2 expression, and inhibit tumor growth by 45%. These in vivo data correlate well with selective effects of pectins on Gal-3-mediated T-cell apoptosis and activation. Our study suggests a novel approach for the development of polysaccharide-based agents that target Gal-3 function.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galactanos/farmacologia , Galectina 3/metabolismo , Panax/metabolismo , Pectinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T , Animais , Linhagem Celular Tumoral , Humanos , Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
19.
Nat Commun ; 10(1): 2681, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213606

RESUMO

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.


Assuntos
Doenças do Sistema Imunitário/prevenção & controle , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Engenharia Celular/métodos , Linhagem Celular Tumoral , Citocinas/imunologia , Fluoresceína/metabolismo , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/metabolismo , Humanos , Doenças do Sistema Imunitário/etiologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Camundongos , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/metabolismo , Síndrome , Linfócitos T/metabolismo , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Hematol Oncol ; 37 Suppl 1: 95-100, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187533

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment for lymphoid malignancies, especially diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). However, there continue to be significant limitations of this therapy, such as incomplete or nonsustained responses and severe toxicities in a subset of patients. Furthermore, expanding the role of CAR T-cell therapy to new disease types is an important next step. In this review, we will highlight landmark trials for anti-CD19 CAR T cells and first-in-human trials of novel CARs, as well as discuss promising innovative CAR designs that are still undergoing preclinical development. Lastly, we will discuss toxicity and mechanisms of CAR T-cell resistance and failure, as well as potential future treatment approaches to these common issues.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19 , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Pesquisa , Resultado do Tratamento
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